Non-Standard Backbone Chemistries Added to the Genetic Code of a Living Organism for Enhanced Peptide Therapeutics

Published in Nature in 2024, this paper addressed a longstanding barrier in genetic code expansion: programming the ribosome to incorporate monomers with fundamentally altered backbone geometry into proteins within a living organism, specifically α,α-disubstituted amino acids and β-amino acids.

Standard amino acids are α-amino acids with a single side chain attached to the alpha carbon. α,α-Disubstituted amino acids carry two substituents on the alpha carbon, creating steric constraints that restrict backbone rotation and enforce defined secondary structures. β-Amino acids extend the backbone by an additional carbon, changing the spacing between peptide bonds. Both classes of monomer confer properties that are highly valued for therapeutic peptides, particularly intrinsic resistance to protease degradation. The body's enzymes evolved to cleave canonical α-amino acid backbones and do not efficiently recognise altered geometries.

The challenge is that the ribosome, the cell's protein-synthesis machine, evolved to handle α-amino acids. Incorporating monomers with different backbone structures requires the ribosome to accommodate substrates that sit differently in its active site. The Chin group engineered the translation system to achieve this, demonstrating that organisms with expanded genetic codes can ribosomally incorporate these non-standard backbone monomers at genetically specified positions.

For Constructive Bio's therapeutic pipeline, this capability is directly relevant to oral peptide programmes and other modalities where protease resistance is critical. Backbone-modified residues provide intrinsic metabolic stability without relying on formulation strategies like enteric coatings or permeation enhancers. An oral peptide containing α,α-disubstituted residues at protease-susceptible positions can survive gastrointestinal transit because the proteases do not efficiently cleave the modified backbone.

This work expands the chemical space accessible through BioForge fermentation beyond side-chain modifications into the peptide backbone itself, a dimension of molecular diversity that solid-phase peptide synthesis can access only with specialised and expensive building block chemistry.